2018 Progress Report and 2019 Update Defeat GBM Research Collaborative Key Personnel: PRINCIPAL INVESTIGATORS • Tim Cloughesy, MD A NOTE FROM THE CEO University of California, Los Angeles • John de Groot, MD MD Anderson Cancer Center Over the past five years, the Defeat GBM Research Collaborative has stood as a testament to the power of ideas, collaboration, and the philanthropic partnership • Frank Furnari, PhD between patient advocacy nonprofits like NBTS and a dedicated community of Ludwig Cancer Research, supporters. University of California, San Diego • Dimpy Koul, PhD When we launched Defeat GBM as our flagship research initiative in 2014, we MD Anderson Cancer Center sought to do something different. Decades of grant-making in the traditional form of funding separate, individual research projects (one- to two-year grants • Ingo Mellinghoff, MD to a single Principle Investigator) had produced extraordinary knowledge of the Memorial Sloan Kettering Cancer Center biology of glioblastoma cells, but not nearly enough of this work was primed to • Paul Mischel, MD move out of research laboratories and into clinical trials for patients. Ludwig Cancer Research, University of California, San Diego NBTS wanted to see what could be accomplished if, instead of continuing this traditional model of research funding, we deep-funded a team of expert • Erik Sulman, MD, PhD researchers, over a five-year period, to work collaboratively. This team would be NYU Langone’s Perlmutter charged with working across the continuum of research to translate a scientific Cancer Center discovery into an actionable treatment strategy and/or medical product that could • Roel Verhaak, PhD be tested in clinical trials, and hopefully become an approved new therapeutic The Jackson Laboratory option for patients. In short, we wanted to change the way glioblastoma research was funded and conducted. It was a big bet, but we believed it would be critical STRATEGIC SCIENTIFIC to accelerating the pace at which we discover, develop, and evaluate new ADVISORY COUNCIL therapies for patients. We made a $10 million commitment to our team of world- • Scientific Director: class Defeat GBM researchers, hopeful that our community would share our vision W. K. Alfred Yung, MD and enthusiasm for an innovative, unconventional initiative aimed at speeding progress against glioblastoma. We are humbled and profoundly grateful that you MD Anderson Cancer Center did. • Anna Barker, PhD Arizona State University Thanks to your generous support, Defeat GBM’s scientific endeavours have led to Mitchel S. Berger MD, FACS, new discoveries about how glioblastoma tumors function and evolve, and how • FAANS they evade current treatments — as well as potential new strategies, methods, and drugs to prevent these tumors from continuing to grow. The Defeat GBM University of California, San Francisco team has tested thousands of drugs preclinically, and identified a number of • Lewis Cantley, PhD useful “biomarkers” to predict which drugs – or types of drugs – are most likely Weill Cornell Medical College to benefit subgroups of GBM patients. Together, we’ve demonstrated what fresh Webster Cavenee, PhD thinking, a shared vision, and novel, responsive philanthropy can accomplish. We • are proud to share these accomplishments with you in the following report. Ludwig Cancer Research • William C. Hahn, MD, PhD With sincere gratitude, Dana Farber Cancer Institute/ David F. Arons, Chief Executive Officer Harvard Medical School LATEST UPDATES: 2018 & 2019 “Over the past four years, we made major progress Making Existing Treatments More Effective towards our goals…our findings are poised to generate clinical impact for patients.” Together, the NBTS-funded Defeat GBM teams from Ludwig Cancer Research in San – Drs. Paul Mischel and Timothy Cloughesy Diego and MD Anderson Cancer Center have discovered, tested, and advanced a new approach to “supercharge” the effects of radiation treatment for GBM patients. They found that combining radiation with a type of drug known as an “FGFR inhibitor” could prevent tumors from repairing themselves following radiation treatment. The team developed laboratory models to test and compare multiple types of these drugs and are planning a clinical trial with the most promising of those tested. Another team from the collaborative discovered that administering a type of immunotherapy (immune checkpoint inhibitors) to patients with GBM prior to surgery (neoadjuvant) could improve the activity of these promising treatments. This research has shown that immune checkpoint inhibitors (like pembrolizumab), could be effective for brain cancer patients if used in the neoadjuvant setting. Importantly, this now provides a rational way to develop immunotherapies for the treatment of brain tumors in future clinical trial programs. Identifying New, Promising Treatments The Defeat GBM team at MD Anderson Cancer “The focus…is to validate and accelerate the translation of high- Center has created 70 new model systems value targets and pharmaceuticals into the clinic,” said the MD that mimic human GBM tumors with superior Anderson Defeat GBM team in their progress report. “Over the last reliability compared to existing laboratory year, we have continued to identify and validate multiple drugs for models. These models have been deployed the treatment of subgroups of patients with GBM.” across the Defeat GBM teams to identify and validate a host of novel disease targets that new treatments could attack and enabled testing of massive libraries of drugs against these targets. These potential new treatment approaches fall into three major categories: precision medicine, targeting vulnerabilities in tumor metabolism, and revealing the hiding places of tumor-causing genes. Precision Medicine Defeat GBM researchers have established multiple potential strategies for combining specific classes of drugs to block the multiple escape routes GBM tumors use to avoid treatment with a single drug. • Identified a combination of drugs (CLK2 inhibitors with PI3K/mTOR or FGFR inhibitors) that can overcome resistance to targeted GBM treatments. • Identified a major signaling pathway (Aurora A kinase/PLK1/CDK1) that drives resistance to PI3K inhibiting drugs. • Identified several targets that could be exploited for potential new treatment approaches in patients with a particularly aggressive subset of GBM tumors (mesenchymal), including one target (LAYN) that looks especially promising. • Discovered that inhibiting a particular protein (DAXX) leads to increased survival in GBM laboratory models missing a specific gene (PTEN). The team is currently screening for drugs that can knockout the protein in relevant lab models. • Found that two different members from a family of drugs (PARP inhibitors) were highly active in killing tumor cells in laboratory studies, and that one of these (pamiparib) has demonstrated the ability to cross the blood- brain barrier — a major hurdle in the treatment of brain tumors. Collectively, these results offer action- able precision medicine strategies that can be followed up on by the field of neuro-oncology research. Targeting Vulnerabilities in Tumor Metabolism Defeat GBM investigators Previously, Defeat GBM researchers have shown that glioblastoma tumors require vast amounts of cholesterol to fuel their growth, and that shutting down their ability to manufacture and retain cholesterol could be a new treatment strategy. The team has now identified at least two other ways in which glioblastoma cells become dependent, or addicted, to certain molecules to fuel their metabolism: • The first involves an enzyme which GBM is dependent on to keep growing (LPCAT1). Knocking-out LPCAT1 in laboratory models led to significant tumor cell death indicating an encouraging new drug target. • The second involves a molecule that is so important to a cell’s metabolism and other functions that healthy cells have three different ways of generating it (NAD). Cancer cells, however, can use only one NAD production pathway, rendering them highly vulnerable to targeted treatments that block that pathway. “I’ve been lucky,” says eight-year GBM survivor, Karen Turner. “But we must continue research to improve treatments, provide a better quality of life for patients, and, of course, find a cure.” Revealing the Hiding Places of Tumor-causing Genes In our last Defeat GBM update, we highlighted the discovery that tumor-causing genes in GBM (oncogenes) are able to “hide” on extrachromosomal DNA (ecDNA). Further research since has revealed additional information about this process, which could lead to new approaches to attack and kill cancer cells. Enable More Personalized Treatments by Gathering Tumor Information via Novel & Less Invasive Techniques The Defeat GBM Research Collaborative is focused on understanding how GBM tumors change and adapt during treatment with the goal of unveiling new therapeutic targets and informing clinical treatment decisions. To do this type of tracking and analysis, researchers and doctors need to perform tests on tumor samples taken via biopsies. However, for brain tumor patients, the prospect of repeated biopsies is often not only extremely risky, but simply not feasible. Accordingly, Defeat GBM researchers have been developing a number of innovative, less invasive approaches to extract more information about how glioblastoma tumors function than ever before: • A method to isolate small fragments of DNA shed from tumors (circulating tumor DNA) in a patient’s cerebrospinal fluid